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Project description:Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes the electron transport chain protein complexes. The final step in CL biosynthesis concerns its remodeling: the exchange of nascent acyl chains with longer, unsaturated chains. However, the enzyme responsible for cleaving nascent CL has remained elusive. Here, we describe ABDH18 as the candidate de-acylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro and its inactivation in cells and mice results in accumulation of nascent CL in serum and tissues. Strikingly, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth Syndrome. This rare genetic disease is characterized by the build-up of MLCL due to inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL remodeling cascade. We also identified a selective, covalent small molecule inhibitor of ABHD18 that restores TAZ mutant phenotypes in patient fibroblasts and fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.
2025-05-29 | GSE276191 | GEO
Project description:Cardiolipin (CL) is the signature phospholipid of the inner mitochondrial membrane, where it stabilizes the electron transport chain protein complexes. The final step in CL biosynthesis concerns its remodeling: the exchange of nascent acyl chains with longer, unsaturated chains. However, the enzyme responsible for cleaving nascent CL has remained elusive. Here, we describe ABDH18 as the candidate de-acylase in the CL biosynthesis pathway. Accordingly, ABHD18 converts CL into monolysocardiolipin (MLCL) in vitro and its inactivation in cells and mice results in accumulation of nascent CL in serum and tissues. Strikingly, ABHD18 deactivation rescues the mitochondrial defects in cells and the morbidity and mortality in mice associated with Barth Syndrome. This rare genetic disease is characterized by the build-up of MLCL due to inactivating mutations in TAFAZZIN (TAZ), which encodes the final enzyme in the CL remodeling cascade. We also identified a selective, covalent small molecule inhibitor of ABHD18 that restores TAZ mutant phenotypes in patient fibroblasts and fish embryos. This study highlights a striking example of genetic suppression of a monogenic disease revealing a canonical enzyme in the CL biosynthesis pathway.
2025-05-29 | GSE297335 | GEO
Project description:ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome
| PRJNA1263869 | ENA
Project description:ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome [CRISPR]
| PRJNA1155664 | ENA
Project description:BackgroundCardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in Tafazzin (TAZ), encoding a mitochondrial acyltransferase required for cardiolipin remodeling. Despite recent description of a mouse model of BTHS cardiomyopathy, an in-depth analysis of specific lipid abnormalities and mitochondrial form and function in an in vivo BTHS cardiomyopathy model is lacking.MethodsWe performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group).ResultsTaz cardiomyocyte-specific knockout mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cardiomyocyte-specific knockout mice exhibited lethality before 2 months of age, with significantly enlarged hearts. More than 80% of cardiomyocyte-specific knockout displayed ventricular dilation at 16 weeks of age and survived until 50 weeks of age. Full parameter analysis of cardiac cardiolipin profiles demonstrated lower total cardiolipin concentration, abnormal cardiolipin fatty acyl composition, and elevated monolysocardiolipin to cardiolipin ratios in Taz cardiomyocyte-specific knockout, relative to controls. Mitochondrial contact site and cristae organizing system and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired. In keeping with observed mitochondrial abnormalities, seahorse experiments demonstrated impaired mitochondrial respiration capacity.ConclusionsOur mouse model mirrors multiple physiological and biochemical aspects of BTHS cardiomyopathy. Our results give important insights into the underlying cause of BTHS cardiomyopathy and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, or other mitochondrial-related cardiomyopathies.
| S-EPMC8210459 | biostudies-literature
Project description:ABHD18 is essential for cardiolipin remodeling and its inhibition restores mitochondrial function in Barth Syndrome [RNA-Seq]
| PRJNA1263536 | ENA
Project description:Barth syndrome (BTHS) is a rare mitochondrial disease that affects heart and skeletal muscle and has no curative treatment. It is caused by recessive mutations in the X-linked gene TAZ, which encodes tafazzin. To develop a clinically relevant gene therapy to restore tafazzin function and treat BTHS, three different adeno-associated virus serotype 9 vectors were tested and compared to identify the optimal promoter-cytomegalovirus (CMV), desmin (Des), or a native tafazzin promoter (Taz)-for TAZ expression following intravenous administration of 1 × 1013 vector genomes/kilogram to a mouse model of BTHS as either neonates (1-2 days of age) or adults (3 months of age). At 5 months of age, evaluations of biodistribution and TAZ expression levels, mouse activity assessments, fatigue in response to exercise, muscle strength, cardiac function, mitochondrial structure, oxygen consumption, and electron transport chain complex activity assays were performed to measure the extent of improvement in treated mice. Each promoter was scored for significant improvement over untreated control mice and significant improvement compared with the other two promoters for every measurement and within each age of administration. All three of the promoters resulted in significant improvements in a majority of the assessments compared with untreated BTHS controls. When scored for overall effectiveness as a gene therapy, the Des promoter was found to provide improvement in the most assessments, followed by the CMV promoter, and finally Taz regardless of injection age. This study provides substantial support for translation of an adeno-associated virus serotype 9-mediated TAZ gene replacement strategy using a Des promoter for human BTHS patients in the clinic.
| S-EPMC6383582 | biostudies-literature
Project description:The biogenesis of mitochondria requires the import of a large number of proteins from the cytosol [1, 2]. Although numerous studies have defined the proteinaceous machineries that mediate mitochondrial protein sorting, little is known about the role of lipids in mitochondrial protein import. Cardiolipin, the signature phospholipid of the mitochondrial inner membrane [3-5], affects the stability of many inner-membrane protein complexes [6-12]. Perturbation of cardiolipin metabolism leads to the X-linked cardioskeletal myopathy Barth syndrome [13-18]. We report that cardiolipin affects the preprotein translocases of the mitochondrial outer membrane. Cardiolipin mutants genetically interact with mutants of outer-membrane translocases. Mitochondria from cardiolipin yeast mutants, as well as Barth syndrome patients, are impaired in the biogenesis of outer-membrane proteins. Our findings reveal a new role for cardiolipin in protein sorting at the mitochondrial outer membrane and bear implications for the pathogenesis of Barth syndrome.
| S-EPMC4329980 | biostudies-literature
Project description:Barth syndrome (BTHS, OMIM 302060) is a genetic disorder caused by variants of the TAFAZZIN gene (G 4.5, OMIM 300394). This debilitating disorder is characterized by cardio- and skeletal myopathy, exercise intolerance, and neutropenia. TAFAZZIN is a transacylase that catalyzes the second step in the cardiolipin (CL) remodeling pathway, preferentially converting saturated CL species into unsaturated CLs that are susceptible to oxidation. As a hallmark mitochondrial membrane lipid, CL has been shown to be essential in a myriad of pathways, including oxidative phosphorylation, the electron transport chain, intermediary metabolism, and intrinsic apoptosis. The pathological severity of BTHS varies substantially from one patient to another, even in individuals bearing the same TAFAZZIN variant. The physiological modifier(s) leading to this disparity, along with the exact molecular mechanism linking CL to the various pathologies, remain largely unknown. Elevated levels of reactive oxygen species (ROS) have been identified in numerous BTHS models, ranging from yeast to human cell lines, suggesting that cellular ROS accumulation may participate in the pathogenesis of BTHS. Although the exact mechanism of how oxidative stress leads to pathogenesis is unknown, it is likely that CL oxidation plays an important role. In this review, we outline what is known about CL oxidation and provide a new perspective linking the functional relevance of CL remodeling and oxidation to ROS mitigation in the context of BTHS.
| S-EPMC9184736 | biostudies-literature
Project description:Tafazzin, which is encoded by the TAZ gene, catalyzes transacylation to form mature cardiolipin and shows preference for the transfer of a linoleic acid (LA) group from phosphatidylcholine (PC) to monolysocardiolipin (MLCL) with influence from mitochondrial membrane curvature. The protein contains domains and motifs involved in targeting, anchoring, and an active site for transacylase activity. Tafazzin activity affects many aspects of mitochondrial structure and function, including that of the electron transport chain, fission-fusion, as well as apoptotic signaling. TAZ mutations are implicated in Barth syndrome, an underdiagnosed and devastating disease that primarily affects male pediatric patients with a broad spectrum of disease pathologies that impact the cardiovascular, neuromuscular, metabolic, and hematologic systems.
| S-EPMC7646589 | biostudies-literature